Phenycyclidine for inducing mydriasis in humans

ABSTRACT

Novel mydriatic compositions containing as the active ingredient a compound of the formula   WHEREIN R1 is hydrogen or lower alkyl, R2 is lower alkyl, or NR1R2 is piperidino, pyrrolidino or hexamethyleneimino R3 is phenyl, thienyl, allyl, vinyl, ethynyl or p-tolyl; lower alkyl as used herein, meaning alkyl group of up to, and including 4 carbon atoms. The novel compositions are characterized by a duration of activity much shorter than that of atropine. They exert a local anaesthetic effect and also act as antidotes to certain myotic substances.

United States Patent 1191 Sokolovsky et al.

[ Dec. 2, 1975 PHENYCYCLIDINE FOR INDUCING MYDRIASIS IN HUMANS 22 Filed:July 30,1973

211 Appl.l lo.:383.905

[30] Foreign Application Priority Data Aug. 7, i972 lsrael 40064 [52]US. Cl. 424/267; 424/244; 424/274 [51] Int. Cl. A61K 31/445 [58] Fieldof Search 424/9, 267

[56] References Cited UNITED STATES PATENTS 3.097,l36 7/1963 Godefroi etal 424/267 3,306,820 2/1967 Krezawoski 424/9 Primary ExaminerJerome D.Goldberg Attorney, Agent, or FirmHubbell, Cohen & Stiefel [57] ABSTRACTNovel mydriatic compositions containing as the active ingredient acompound of the formula wherein R is hydrogen or lower alkyl, R is loweralkyl, or NR R is piperidino, pyrrolidino or hexamethyleneimino R isphenyl, thienyl, allyl, vinyl, ethynyl or p-tolyl; lower alkyl as usedherein, meaning alkyl group of up to, and including 4 carbon atoms. Thenovel compositions are characterized by a duration of activity muchshorter than that of atropine. They exert a local anaesthetic effect andalso act as antidotes to certain myotic substances.

4 Claims, N0 Drawings PHENYCYCLIDINE FOR INDUCING MYDRIASIS IN HUMANSBACKGROUND OF THE INVENTION Heterocyclic amine compounds of the generalformula wherein R is pyrrolidino, piperidino or hexamethyleneimino, andthe preparation thereof, are known from British Patent No. 836,083. Thecompounds of this type are known to produce a depressant like effect onthe central nervous system when administered to animals or humans. Theyare stated to be anaesthetic agents per se and useful as adjuncts inanaesthesia. US. Pat. No. 3,097,136 describes compounds of the aboveformula wherein R is wherein R and R are hydrogen or alkyl, or where Rand R taken together form a polymethylene radical of 4 to 6 carbonatoms. These compounds are also stated to effect a depressant-likeeffect on the central nervous system.

A compound of the above general formula, wherein R is a piperidinogroup, is known under the generic name Phencyclidine. This compound hasbeen used for some time as an anaesthetic agent for i.v. use, but itseems that due to some undesired side-effects its use has decreased.

BRIEF SUMMARY OF THE INVENTION The present invention relates to novelmydriatic compositions. More particularly, it relates to novel mydriaticcompositions, which contain as the active ingredient, phencyclidine,certain derivatives or analogues thereof. The invention further relatesto ophthalmological preparations which exert a mydriatic activity whichis characterized by a rapid onset of activity and by a relatively shortduration. Furthermore, the present invention relates to novelcompositions which are useful as antagonists to the myotic activity ofcertain compounds, such as organo-phosphorus compounds and the like.Other, and further aspects of the present invention will become apparenthereinafter.

DESCRIPTION OF A PREFERRED EMBODIMENT According to the present inventionthere are provided novel ophthalmic preparations, and especiallyophthalmic solutions, containing as the active ingredient compounds ofthe general formula wherein R is hydrogen or lower alkyl, R is loweralkyl, or NR R is piperidino, pyrrolidino or hexamethyleneimino. Theterms lower alkyl as used herein means alkyl of up to and including 4carbon atoms; R is phenyl, thienyl, allyl, vinyl, ethynyl, p-tolyl; andsuitable pharmaceutically acceptable salts thereof.

The ophthalmic compositions according. to the invention contain fromabout 0.02 to about 2.0 by weight of the above active ingredient,together with suitable adjuvants and other components, for adjusting thepH and the like. The novel ophthalmic compositions according to theinvention also exert a certain local an aesthetic effect on the parts ofthe eye in conctact therewith, the intensity of this effect depending onthe specific derivative and the quantity used. This combination ofmydriatic effect and local-anaesthetic effect is of advantage forvarious purposes, as only one instead of two preparations is necessaryto obtain both effects.

The onset of the mydriatic effect is quite rapid, and the maximum effectis attained with some preparations within 3 minutes.

The compounds of the present invention are prepared by conventionalmethods known from the literature, and also from the above citedpatents.

The process for preparing some of the active piperidino compoundsdefined above, comprises reacting a l-piperidinocyclohexanecarbonitrilewith a Grignard alkyl halide of the formula RMgX.l-( l-phenylcyclohexyl)piperidine was prepared according to the procedure set out in BritishPatent No. 836,083.

Compounds of the above formula, wherein R H R lower alkyl and R isphenyl were prepared according to the procedure of Kalir et al.,.l.Med.Chem.l2 (1969), 473. Compounds wherein R and R are lower alkylwere prepared according to Maddox et al., J.Med.Chem, 8 (1965) 230.

The following Examples are to be construed in a nonlimitative manner.

EXAMPLE 1 3.46 kg. of 1-piperidinocyclohexanecarbonitrile in 9 liters ofbenzene are added with stirring to a refluxing solution of phenylmagnesium bromide prepared from 1.094 kg. of magnesium tumings and 7.065kg. of bromobenzene in 22.4 liters of ether. After the addition has beencompleted, about one half hour, the reaction mixture is allowed to standat room temperature for 16 hours. The ether is removed by distillation,the residue cooled and 25.5 liters of 2 N hydrobromic acid added to theresidue. About 20 liters of ether are added to the mixture and it isallowed to stand at 0C. for about 16 hours. The crystallinel-(l-phenylcyclohexyl) piperidine hydrobromide is collected andsuspended in 4 liters of 3 N hydrobromic acid. The mixture is cooled to10C and the crystalline l( l-phenylcyclohexyl)-piperidine hydrobromidecollected; m.p. 2l42l8C. This product can be purified further byrecrystallization from a methanol-ether mixture.

4.2 kg. of 1-(1-phenylcyclohexyl)piperidine hydrobromide are slurriedwith water at C and then treated with 770 g. of sodium hydroxide in 5 l.of water, 16 l. of benzene are added to the mixture with stirring andthen 300 g. of diatomaceous earth are added. The mixture is filtered andthe organic layer separated. The aqueous layer is extracted with a totalof 8 l. of benzene and the benzene extract is added to the main organiclayer. The organic extracts are dried over anhydrous sodium sulfate,charcoaled and filtered. Most of the solvent is removed by distillationin vacuo and the residue treated with 2 l. of methanol. The mixture isallowed to stand for about 16 hours and then the crystallinel(l-phenylcyclohexyl)piperidine collected; m.p. 4646.5C.

2.3 kg. of 1-(1-phenylcyclohexyl)piperidine are dissolved in 3.45 l. ofa mixture composed of one third benzene and two thirds anhydrous ether.The resulting solution is saturated with dry hydrogen chloride gas,cooled and the crystalline l-(l-phenylcyclohexyl)- piperidinehydrochloride collected and washed with anhydrous ether; m.p. 243244C.

EXAMPLE 2 Preparation of l-(1-p-tolylcyclohexyl)piperidine A quantity of43 g piperidine was added dropwise to 42 ml of concentrated hydrochloricacid in 100 ml water, at C. The addition was effected under constantstirring. At the end of the addition, the pH was adjusted to pH 3.0 byadding aqueous hydrochloric acid. There were added 50 g of cyclohexanoneand after this 27 g sodium cyanide in 150 ml water. The solution wasstirred during the addition, and for 2 hours thereafter. After standingovernight, there was formed a precipitate, which was filtered off,washed with a small quantity of cold water, and dried. There wereobtained 86 g of 1-piperidinocyclohexanecarbonitrile, M.P. 65-68C.

A Grignard reagent was prepared from p-bromotoluene by adding dropwise85 g p-bromotoluene in dry ether to 13 g of magnesium shavings in dryether. At the end of this reaction, there was added under cooling andwith constant stirring a solution of 80 g of the compound obtained inthe first stage, in ether. A heavy precipitate was formed. After theaddition, the reaction mixture was left to stand for 3 hours. Thecomplex was decomposed by the addition of a concentrated solution ofammonium chloride. Two layers were formed, and from the etheral layerthe p-tolyl analogue of phencyclidine was extracted with an aqueoussolution of hydrochloric acid. The free base was obtained by addingammonia and ether and the ethereal solution was distilled afterevaporation of the ether. The m.p. was 67C, yield 40% calculated on thecarbonitrile. The m.p. of the hydrochloride was 217C. Elementalanalysis: C, 73.5%; H, 10.1%; N, 4.9%; chlorine: 12.2%. Thin layerchromatography gave an R; value of 0.2 (acid alumina/chloroform) and 0.7(neutral alumina, chloroform/ benzene 1: l

EXAMPLE 3 N-ethyll -phenylcyclohexylamine EXAMPLE 4 N-Methyll-phenylcyclohexylamine Phenyllithium was prepared from lithium wire(36.4g., 52 g.-atoms) and bromobenzene (376 g., 2.4 moles) in a total of1900 ml. ether. To this was added N-cyclohexylidenemethylamine (165 g.,1.48 moles) in 300 ml. of anhydrous ether over a period of 45 min. After3 hr. at reflux, 1.5 l. of water were added, and the ether layer wasseparated, water washed, and dried (MgSO After removal of ether theresidue was distilled. There were obtained 298 g. (65%) of product, b.p.76-78 (150 u). Infrared analysis showed no absorption characteristic ofthe CN bond.

The hydrochloride was prepared by treating the base in ether the HCl,m.p. ll86.

Anal. calculated for C H CIN: C,69.l6; H,8.93. Found: C, 69,09; H, 8.90.

EXAMPLE 5 N,N-Dimethyll -phenylcyclohexylamineN-Methyl-l-phenylcyclohexylamine (188 g., 0.993 mole) and formic acid(102 g., 2.22 moles) were mixed, and to the solution was added 87 g. of38% formaldehyde. A vigorous exothermic reaction took place. Thereaction mixture was then warmed on a steam bath for 1 hr., basifiedwith 5 N NaOH, and extracted with ether. After drying the solution andremoving the ether, the residue was distilled in vacuo. The product wasobtained in a yield of 168 g. (83%), b.p. 969 8 (50-60 pt). The liquidreadily crystallized, m.p. 4244.

Physiochemical data of compounds wherein R is hydrogen or lower alkyl, Ris lower alkyl, or where R and R designate C I-I and wherein R is phenylare given in the following Table:

TABLE I MP. R, No. R, R (Q A B l H CH; 186 0.2 0.3 2 CH CH, 166 0.3 0.5

A Acidic alumina 3 H C H 235 0.2 0.3 (Woelrn)- chloroform. 4 H iC H 23305 0.7 B Neutral alumina (Woelm)- 5 -C H 238 0.4 05 chloroform.

In an analogous manner various other derivatives were prepared, and thedata for these derivatives are given in the following Table 11:

TABLE II.

A: Acid Alumina (Woclm). chloroform; B: Neutral alumina (Woclm)chloroform/benzene. 111; C: Silica (Woclm) methanol/methylenechloride/acetic acid: l:l:l

Ophthalmic solutions were prepared, and the effect 9 of variations ofconcentration, pH and other factors were determined. Itwas found thatthe best effects are attained at a pH of about 7.0 to 8.0. Above pH 8.0the solubility of the compounds used was not great enough.

The experiments were carried out first on eyes of test animals, such asmice and guinea pigs. Aft gvards, experiments were conducted on monkeysand also on humans.

The solutions of pH 7.4 (0.1 M phosphate buffer) of variousphencyclidine derivatives were tested at various concentrations; Aminimum concentration of l' M of phencyclidine was required for themydriatic effect. Onset time was about 2 minutes from the application inthe form of drops directly into the eye. This compares with aboutminutes onset time of 10 M atropine. The duration of the maximum effectwas about minutes, and after the effect subsided during a further 15minutes to normal. An antagonism against cholinergic compounds wasobtained with phencyclidine, while none was observed with atropine. Theduration of the effect of atropine lasted for more than 2 hours. At aconcentration of 1O M local anaesthesia of the eyeball was obtained withphencyclidine, and none with atropine.

Similar experiments were conducted with various derivatives andanalogues of phencyclidine, and some of these are presented in thefollowing Table III:

The solutions were in phosphate buffer (pl-I 7.4), and it is clear fromthe above data that the most effective are the compounds of group I,namely phencyclidine, the thienyl derivative, the p-methyl (i.e.,R=tolyl) derivative and the ethynyl derivative. The drops were appliedto mice eyes, one of the eyes serving as a control. The examination wascarried out with a binocular microscope of 20x magnification understrong illumination.

The following Table IV illustrates the effect of changes of pH on themydriatic effect:

Dependance of Mydriatic Effect on pH TABLE IV.

Phencyclidine (M) pH I-ICl Atropine (M) not active active (-H-) veryactive From the Table it is clear that at a pH below 7.0 the mydriaticeffect disappears, and that quatemization also results in lack ofmydriatic effect.

From the above it is clear that phencyclidine, and some of itsderivatives, and especially the Z-thienyl, ptolyl and ethynylderivatives, are effective mydriatics,

TABLE III Onset time Degree of Duration Antago- Compounds (min.) theeffect (min.) nism Group'l (l0 M) R= l. 10"M AcCH 2 maximum 10-15 2i 5l0""M Q l S 3 l-IC I C Group II (lO' M) R= CH CH CH, CHCl-I C H 2 of the4 lO' M AcCH maximum 2" Group III (l0 M) R= Inactive as mydriatics andthat these have various advantages as compared with the conventionalmydriatic, atropine. Onset of the maximum effect is much more rapid(less than minutes for a maximum effect as compared with about up to 30minutes for atropine), Duration is of comparatively brief period (aboutminutes of maximum effect, and decrease to normal after a further 15minutes, as compared with more than 2 hours till normal with atropine).When atropine is applied to the human eye, the patient is hindered inmany normal activities, such as driving a car, for a prolonged period oftime, (1-2 days). When phencyclidine or its derivatives is applied, thisperiod is much shorter, and thus the patient can return to normalactivity within a short time after examination by the physician. It ispossible to apply ophthalmic drops containing phencyclidine or one ofits derivatives twice, if the duration of the effect is too short toenable completion of the examination. Within a short time after thecompletion of the examination the mydriatic effect disappears and thepatient can resume any normal activity.

The active ingredient is advantageously used as a salt (and especiallyas hydrochloride), and concentrations of from about 0.02 to 0.2% byweight were found to be satisfactory. The pH is adjusted to about7.3-7.7 by the use of any acceptable buffer, and especially by phosphatebuffer. The ophthalmic solutions according to the invention may containother ingredients, such as benzalkonium chloride or the like.

Experiments have shown that cholinergic drugs have a pronouncedantagonistic effect againsts the mydriatic activity of the compositionsaccording to the invention. The antagonism was tested with a number ofcompounds of the above general formula, and data obtained withphencyclidine are given hereinafter, to illustrate this effect. It isclear that cholinergic drugs can be used as effective antidotes to theeffects brought about by the compositions of the invention.

It is clear that the above is by way of example only and that thepresent invention relates to ophthalmic compositions for use asmydriatics and also as antagonists against certain myotic substances,said compositions of matter containing an active ingredientphencyclidine or a derivative thereof of the type exemplified, andespecially the 2-thienyl, the p-methyl (p-tolyl), the allyl and theethynyl analogues, as well as other suitable analogues of the same type.

8 TABLE v CHOLlNERGlC DRUGS AS ANTIDOTES TO MYDRlATlC ACTIVITY OFPHENCYCLID INE AGENT A. Acetylcholine Antagonist l. Oxotremoline 6 l l2. Arecoline 3. 3-acetoxyquinuoclidine B. ChE-inhibitors 4. Eserine I X5. Tacrine l X 6. Phospholine l X To antagonize 10 M phcncylidinc(minimal dose) EXAMINATION OF ANTAGONISTIC EFFECT 3 minutes after localapplication of 10 phencyclidine (pH 8.0, 0.1 M phosphate buffer) a dropof the tested buffered drug solution was locally dropped on the sameeye. The pupil diameter was measured (binocular microscope X 40), andcalculated as percent of the whole eye diameter.

TIME"""" /z (Pupil diameter) After l0' M arccolinc local application.

What is claimed is: 1. A method of inducing mydriasis in humans forexamination purposes, which comprises applying phencyclidine to an eyein an amount effective to dilate the pupil of the eye treated therewith.

2. The method of claim 1, wherein the phencyclidine is applied in theform of an ophthalmic solution con-.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 923,990 Dat d Decem er 2, 1975 Inventor(s) MOrdechai and Saul It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Title page, line 4 after the formula, in the Abstract:

"meaning alkyl" should read meaning an alkyl Column 2, line 15:"conctact" should read contact line 58: "l(l-phenylcyclohexyl) shouldread l-(lphenylcyclohexyl) Column 3, line 7: "1(l-phenylcyclohexyl)piperidine" should read l-(l-phenylcyclohexyl) piperidine line 45:"etheral" should read ethereal Column 5, line 29: "after the" shouldread after this the Column 7, line 33: "againsts" should read againstSigned and Scaled this m [SEAL] D y0fApn11976 A ttes r:

RUTH C. MASON Arresting Officer C. MARSHALL DANN Commissioner oj'latenrsand Trademarks

1. A METHOD OF INDUCING MYDRIASIS IN HUMANS FOR EXAMINATION PURPOSES,WHICH COMPRISES APPLYING PHENCYCLIDINE TO AN EYE IN AN AMOUNT TO DILATETHE PUPIL OF THE EYE TREATED THEREWITH.
 2. The method of claim 1,wherein the phencyclidine is applied in the form of an ophthalmicsolution containing from about 0.02 to 0.2% by weight of phencyclidineand a buffer in an amount sufficient to adjust the pH of the solution to7 to
 8. 3. The method of claim 2, wherein the pH of the solution is7.3-7.7.
 4. The method of claim 2, wherein said buffer is a phosphatebuffer.